1. Introduction

Fucus vesiculosus L. (bladderwrack) grows on rocky shores in areas with cold and temperate climate, mostly at North American and Western European shores of the North Atlantic and the Pacific Ocean (Verhelst 2010). Fucus vesiculosus is a small brown seaweed measuring

20 to 100 centimetres in length. Their flat thallus branches dichotomously. Oval with air filled bubbles in the membraneous parts make the seaweed float vertically. This seaweed is harvested at the start of summer (Verhelst 2010, De Smet et al. 1997).

−Polyphenols: ca. 15%, composed of phloroglucinol units. Most are high in molecular weight (25% greater than 10,000), phlorotannins consisting of carbon-carbon or ether linked phloroglucinol units in linear chains with numerous side branches. Lower molecular weight polyphenols with 4 to 7 phloroglucinol units, such as fucols (carbon-carbon linked) and fucophlorethols (one carbon-carbon and one or more ether links) have been isolated as well as free phloroglucinol (British Herbal Compendium 1992).

2. Historical data on medicinal use

2.1. Information on period of medicinal use in the European Union

Fucus vesiculosus was already known by the Romans, in those times it was used against joint complaints. From the 16th century on, Fucus vesiculosus was used in China to treat goitre caused by iodine deficit. In the 17th century, Fucus vesiculosus was used in France to treat goitre and other thyroid complaints. This was also the case for the United Kingdom with the additional indication of corpulency treatment. In the United States, it was also indicated for psoriasis and as a strengthening agent. During the 18th century, Fucus vesiculosus was used to treat asthma, goitre and skin diseases (Morel et al. 2005, Verhelst 2010). Other applications were treatment of rheumatism and slimming baths, but the latter is questionable (Delfosse 1998).

Ulbricht et al. (2013) made an overview of experimental and traditional use of Fucus vesiculosus as monotherapy or in combination. Experimentally investigated properties can be found in the preclinical section. Among the pathological conditions wherein the use of seaweed or its components is reported are: acne, enhanced blood clotting tendency, atopic dermatitis, breast diseases (mastalgia, menopausal syndrome, dysmenorrhea, fibroadenomatosis), burns, hyperglycemia and overweight. Most of the information on humans is unclear or of conflicting scientific evidence.

Fucus vesiculosus is used as a natural source of iodine. The iodine content gives some plausibility to a possible stimulating effect on the thyroid gland. There is the connotation of an increased burning of fat (Weiss and Fintelmann 1999). Some sources are warning against latent hyperthyroidism if Fucus preparations are administered for a long time (Verhelst 2010). It has even been mentioned that iodine in Fucus can cause a thyreotoxic crisis and hypersensitivity reactions (Weiss and Fintelmann 1999, Van Hellemont 1985). However it should be noted that the iodine content is variable in seaweeds (Tyler 1993, De Smet et al. 1997). This variability as well as the daily intake of iodine make predictions difficult.

2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications

Austria

In Austria Fucus is only present in homeopathic medicinal products.

Belgium

As far as medicinal products are concerned, the substance was included in a range of “ancient” herbal teas of varying composition. It was also included in various combination products used as laxatives.

Upon request, a list of 453 food supplements was received as a result of a query (“Fucus vesiculosus”) done by the National Competent Authority for food supplements in Belgium (FAVV). The information is not very conclusive as the herbal substance/preparation is not always (almost never) mentioned on the list and can therefore not be further characterised. An analysis of the list indicates that the substance is mostly used in food supplements with claims refering to “minceur”, “silhouette”, “detox”. Notifications only go back to 1990 in Belgium.

Bulgaria

There are no products containing Fucus vesiculosus with marketing authorisation or registration in Bulgaria. No information on food supplements is transmitted.

Denmark

One product containing Fucus vesiculosus is listed in the Danish Food and Veterinary Agency list of food supplements. The product is a combination product with Lucerne (Medicago sativa L.) and is sold as an iodine supplement.

Estonia

There are no authorised medicinal products on the market in Estonia. Other products containing this seaweed are probably classified as food supplements, under notification at the Veterinary and Food Board.

Finland

Fucus has not been registered as traditional herbal product in Finland, and there is no marketing authorisation as WEU medicinal product either. As the food supplement market is vast and unsteady, it is difficult to know if currently there is Fucus on the market as food supplement. According to the food supplement list from November 2011, there is one food supplement containing, among other ingredients, Fucus vesiculosus.

France

Galenic form: hard capsules with 130 mg powder of Fucus vesiculosus.

Posology for adults only: 1 capsule 2 times daily.

Therapeutic indication: Traditionally used as an adjuvant to slimming diets.

No pharmacovigilance actions were taken towards this product. On the market since 1981.

Greece

There are not any marketed products contaning Fucus as simple ingredients and/or in combinations.

The Netherlands

There are no WEU authorised/TU registered herbal medicinal products in the Netherlands containing Fucus vesiculosus as a single active ingredient, neither combination products. No data on the use of this seaweed in food supplements are available.

In adolescents over 12 years of age and adults, the single dose (=daily dose) is 1.7 – 2.5 g (51 –

75 mg of Fucus vesiculosus) before sleep. The daily dose should not be exceeded. The use in children under 12 years of age is contraindicated.

Use more frequently than 2 to 3 times weekly is not recommended. The duration of use should not exceed 1 to 2 weeks.

Indications: As a laxative for short-term use in constipation. Risks (adverse drug effects, literature):

Abdominal pains, abdominal cramps, watery stool, especially in patients with irritable colon syndrome. On prolonged use: electrolyte and water balance disorders which potentiate the action of cardiac glycosides, medicinal products inducing reversion to sinus rhythm (e.g. quinidine) and medicinal products inducing QT prolongation; albuminuria and hematuria. Pseudomelanosis coli and pH- dependent red-brown or yellow discoloration of urine may occur. In hypersensitive individuals, photoallergy manifesting with rush and erythema may occur due to the content of St. John’s Wort. In patients with gastroesophageal reflux, heartburn may increase.

Portugal

There are no authorised products on the market. INFARMED, I.P. is the national authority only for medicines and healthcare products. No information can be given about the existence in the market of food supplements with this seaweed.

Romania

Regarding Fucus there are no products authorised by National Agency for Medicines and Medical Devices.

Spain

Monopreparation

Registered product for TU

Fucus vesiculosus powdered substance 100 mg

Hard capsules for oral use, on the Spanish market since 1988. Posology: 100 – 300 mg per day

Indication: adjuvant in diets for weight control by causing a decrease in appetite No pharmacovigilance actions were taken on this products.

AEMPS is responsible for medicinal products only; hence no information can be given about the existence on the market of food supplements with Fucus vesiculosus.

Sweden

There are no authorised products on the market in Sweden.

United Kingdom

Since 1968 there are a number of authorised products containing Fucus on the market in UK. These will all be transferred soon to the traditional category and will have indications along the lines of: “A traditional herbal medicinal product used as an aid to slimming as part of a calorie controlled diet,

based on traditional use only”. All preparations have to be considered as already being on the market before 1980.

The composition of the different combination products are given below:

Product (capsule) containing

Powdered Fucus (Fucus vesiculosus L.) 100 mg

Alginic acid 200 mg

Hypromellose capsule 75 mg

Indication: traditional herbal remedy used as an adjuvant to slimming diets to help weight loss. Posology: 1 capsule, 1 to 3 times daily during 3 weeks to be taken with a glass of water before meals. The treatment should be limited to 3 weeks.

Not recommended for children under 12 years of age. Date of first authorisation (renewal): 29 August 1997.

Indication: A traditional herbal remedy to help in the treatment of obesity and the symptomatic relief of rheumatic pain.

Posology: Adults: 2 tablets to be taken orally morning and evening. Not recommended for children under 12 years of age-. Elderly patients: normal adult dose.

Date of first authorisation: 20 March 1991.

Product (tablet) containing

Fucus Dry Extract 5:1 120 mg Indication: an aid to slimming.

Posology: to be taken by mouth. Adults (16 years and above) and elderly: 1 tablet 3 times a day. This product should be taken as part of a calorie-controlled diet.

Date of first authorisation: 20 May 1999.

Product (tablet) containing

Fucus Aqueous Powdered Extract 5:1 120 mg

Indication: a herbal remedy traditionally used as an aid to slimming.

Posology: to be taken orally. Elderly, adults and adolescents over 16 years of age: 2 tablets to be taken with water 3 times a day.

Not recommended in children and adolescents under 16 years of age. Date of first authorisation: 30 March 2009.

Product (tablet) containing

Fucus vesiculosus BHP 500 mg

Indication: a herbal remedy traditionally used as an adjunct with calorie control for weight reduction. Posology: for oral administration. Adults and Elderly: 2 to 3 tablets to be taken with a tumbler of water, half an hour before meals.

Not recommended for children.

Date of first authorisation: 1 July 2004.

Reference is made to following literature sources:

The British Herbal Pharmacopoeia (1983) contains a monograph on Fucus (bladderwrack). The herbal substance is described as containing… Small variable amounts of iodine…, referring to the Martindale 25th edition (Todd 1967) with an upper limit for iodine of 0.2%.

The following therapeutic indications are mentioned: myxedema, lymphadenoid goiter, obesity, rheumatism and rheumatoid arthritis. A specific indication is mentioned: obesity associated with hypothyroidism.

Preparation and posology (trice daily):

Dried thallus. Dose: 5-10 g OR by infusion.

Liquid extract in 25% ethanol. Dose: 4 to 8 ml.

The Martindale describes the following (Todd 1967):

Preparation and posology:

Soft extract prepared with ethanol (45%). Dose: 200 to 600 mg.

Liquid extract prepared with ethanol (45%). Dose: 4 to 8 ml.

The number of daily intakes is not mentioned.

The British Herbal Compendium (1992) describes Fuci thallus as an anti-obesic, a thyroactive, an antirheumatic and a demulgent. The therapeutic indications are: (1) obesity associated with iodine deficiency and hypothyroidism and (2) lymphadenoid goitre.

Preparation and posology (daily):

Dried thallus. Dose: 0.8 to 2 g

Liquid extract (1:1, ethanol 25%). Dose: 1-2 ml

Tincture (1:5, ethanol 25%). Dose: 4-10 ml.

Indication: A herbal remedy traditionally used for the treatment of obesity.

3. Non-Clinical Data

In order to get an overview of the different activities, a summary table is included (Table 2). Most of the activities are not related to the therapeutic indication of the monograph. Their value is therefore often limited. In the following more detailed presentation of preclinical data, a difference is made between the investigated properties related to the therapeutic indication of the monograph and those which are of a more general interest.

Table 2: Summary of in vitro experiments

Fucus vesiculosus contains variable amounts of iodine of which the risks and benefits have to be taken into account. A short overview of the incorporation of iodine into the thyroid hormones is described, as well as the metabolism of thyroid hormones. A schematic representation is given in Fig. 2 and 3.

Iodine and formation of thyroid hormones

Figure 2: (Iodine is transported from the blood compartment to the thyroid gland, to be reduced by peroxidase and subsequently incorporated into the amino acid thyrosine. This process is inhibited by iodides. Mono-iodothyroxine (MIT) and di-iodothyroxine (DIT) are are formed. Two units of DIT are fused to tetra-iodothyroxine (T4) or thyroxine (according to Katzung 2004, DiPiro et al. 2005)).

Figure 3: Thyroxine (T4) can be activated peripherally to 3,5,3’-triiodothyronine or T3, which is 3 to 4 times more potent than T4. It can also be deactivated to 3,3’,5’-triiodothyronine (reverse T3) (according to Katzung 2004).

In vitro experiments related to the therapeutic indication of the monograph

•α-amylase and α-glucosidase activity

The study by Roy et al. (2011) showed that phlorotannins from Fucus vesiculosus had low IC50 values and high maximum inhibition rates of α-amylase and α-glucosidasein vitro. This demonstrated that phlorotannins from Fucus vesiculosus may be potent inhibitors of both α-amylase and α-glucosidasein vitro. Because α-amylase and α-glucosidase are of great importance in the breakdown of carbohydrates, the authors concluded that phlorotannins might be useful in modulating plasma glucose

and insulin levels after a meal if phlorotannins also showed these effects in vivo. This could be a plausible hypothesis for a mechanism of action to justify clinical studies with (pre)diabetic patients.

•Effect on advanced glycation end product accumulation

In the study by Liu and Gu (2012), the statistical significance (p<0.05) of the results was determined using one way ANOVA and the Tukey-Kramer HSD test. This in vitro study showed that addition of phlorotannins from Fucus vesiculosus to a mixture consisting of albumin and glucose or methylglyoxal inhibited protein glycation significantly (p<0.05). Glucose and methylglyoxal are a substrate and an active intermediate in protein glycation, respectively. Furthermore the study showed that phlorotannins from Fucus vesiculosus significantly (p<0.05) decreased the methylglyoxal content in vitro. The authors suggested that the mechanism by which phlorotannins from Fucus vesiculosus inhibit the formation of advanced glycation end products (AGEs) is by scavenging reactive carbonyls that otherwise would glycate proteins. It needs to be noted that in both experiments the activity of the phlorotannins is low compared to that of phloroglucinol or aminoguanidine. The clinical relevance of the effect is unclear.

In vitro experiments not directly related to the therapeutic indication of the monograph

• Effect on skin models

The results of the study of Thring et al. 2009 showed an anti-collagenase activity by Fucus vesiculosus. Its anti-elastase activity was mild and it had slightly anti-oxidative properties. These effects could be useful, but it is not known whether Fucus vesiculosus extracts are able to penetrate in sufficiently high concentrations through the skin. As a consequence, the clinical relevance of this study is limited.

In the study by Fujimara et al. (2000), the Student t-test was performed to test whether the results are significant (p<0.05) and every experiment was conducted at least twice. The results of the

experiment showed that the high polar fraction and fucoidan from Fucus vesiculosus significantly (p<0.05) stimulated gel contraction and increased the integrin α2β1 expression on fibroblasts compared to control. The authors suggested that the increase in gel contraction arises from an increased integrin α2β1 expression and that the high polar fraction of Fucus vesiculosus contains fucoidan.

It needs to be noted that the exact chemical structure of the active fucoidan remains unknown. A drawback of this study is that an in vitro model of dermal tissue was used. The consequence is that it is unknown to what extent the extracts penetrate the epidermisand reach the dermis in clinical conditions. This limits the clinical relevance of the study.

The article of Rupérez et al. 2002 showed that the antioxidant capacity from Fucus vesiculosus might be attributed to fucans and not only to the polyphenols (Table 2 and 3). The article of Diaz-Rubioet al. (2009) suggested that polyphenols play the key role in the antioxidant capacity. Anyhow, these two articles suggested that Fucus vesiculosus might be used as a source of natural antioxidants (Table 4).

In the study by O’Sullivan et al. 2011, repeated measures ANOVA combined with Dunnett’s or Tukey’s test were used to test if the results are statistically significant (p<0.05 or p<0.01). The ferric reducing antioxidant activity, radical scavenging activity and the prevention of β-carotene bleaching are all measures of protection against free radicals. This study showed that the extracts of Fucus vesiculosus

displayed all three above-mentioned activities. Both catalase and superoxide dismutase are important enzymes in neutralising free radicals. In this experiment the activity of neither catalase nor superoxide dismutase increased significantly. Reduced glutathione (GSH and consists of glutamine, cysteine and glycine) has a key role in non-enzymatic antioxidant activity. This study showed that the levels of GSH in cells treated with extracts from Fucus vesiculosus increased significantly (p<0.05). H2O2 causes DNA damage in cells. This study showed that in cells treated with extract from Fucus vesiculosus the H2O2-induced DNA damage decreased significantly (p<0.05). The overall conclusion of all the experiments conducted by O’Sullivan et al. was that extracts from Fucus vesiculosus showed significant (p<0.05) anti-oxidant activity in vitro. However, it needs to be noted that the antioxidant activity of Fucus vesiculosus extracts is much lower than the one of ascorbic acid.

The study performed by Parys et al. 2010 did not mention if a statistical analysis had been carried out to determine whether the results were statistically significant. The study compared the radical scavenging activity of phloroglucinol, which is known to scavenge radicals, to three fucophlorethols isolated from Fucus vesiculosus. All analysed fucophlorethols showed radical scavenging activity comparable to that of phloroglucinol.

These experiments are typical for screening purposes. Fucus vesiculosus seems to have antioxidative properties in vitro, but the activity is lower than the one of ascorbic acid. The therapeutic consequences are not clear and should be clinically investigated.

•17β-estradiol and progesterone levels and aromatase activity

To test the significance (p<0.05) of the results obtained in the study by Skibola et al. (2005) two-way ANOVA combined with Dunnett’s was used and 2-sided paired t-tests were performed. The experiments performed by Skibola et al. (2005) showed that 50 and 75 µmol/l Fucus vesiculosus dose- significantly (p=0.03) reduced 17β-estradiol levels in human granulosa cells. The observed inhibition was concentration-dependent. These results suggested that Fucus vesiculosus either inhibited 17β- estradiol production or stimulated its breakdown. The inhibition of progesterone production was less prominent, and appearantly there was no concentration-response relationship. On the other hand, there was a clearcut concentration-dependent occupancy of the oestrogen and progesterone receptors.

The results suggested that certain components of Fucus vesiculosus compete with estradiol and progesterone for binding to their receptors and that there are components in Fucus vesiculosus that are antagonists of estradiol and progesterone. In the in vitro study by Parys et al. 2010, the IC50 values of fucophlorethols from Fucus vesiculosus for the enzyme aromatase showed that these fucophlorethols inhibited aromatase. Aromatase turns androgens into estrogens and estrogens play a key role in estrogen-dependent cancers. These in vitro results suggested according to the authors that fucophlorethols from Fucus vesiculosus might be used in the prevention and/or treatment of estrogen- dependent cancers. However, this needs further investigation, because this effect may arise from unspecific interaction of fucophlorethols with aromatase and it is unclear whether the effect would also be present in vivo.

The overall conclusion of both studies is that the activity of Fucus vesiculosus on oestrogen and progestagen receptors and production needs to be further clarified non-clinically as well as clinically. For the time being, the results are not considered relevant for the monograph.

•Effects on coagulation

In the study by Trento et al. 2001, the Dunnett’s test was used to determine the statistical significance (p<0.05) of the results. This study showed that fucansulfate in vitro significantly (p<0.05) and dose- dependently inhibited the production of thrombin compared to control. Thrombin induced platelet aggregation. The study by Trento et al. also showed that in vitro fucansulfate significantly (p<0.01) decreased the platelet aggregation induced by thrombin.

In the study performed by de Azevedo et al. 2009, the statistical significance (p<0.05) of the results was determined using ANOVA combined with Tukey-Kramer tests. This study tests the activated partial thromboplastin time and the prothrombin time, which are both measures for coagulation, in the presence of Fucus vesiculosus extracts. The results showed that these extracts significantly (p<0.001) prolonged both the activated partial thromboplastin and prothrombin time compared to control. However in both experiments this prolongation was much lower than that caused by low molecular weight heparins.

The study carried out by Kwak et al. 2010 did not mention if an analysis to determine the statistical significance of the results had been performed. The results showed that fucoidan from Fucus vesiculosus inhibited ADP-induced aggregation of platelets. This inhibition increased with increasing concentrations of fucoidan and was approximately 2 times stronger than that of heparin. The study also showed that fucoidan from Fucus vesiculosus inhibited the activities of both thrombin and factor Xa. These inhibitions increased concentration-dependently, but was much lower than that of heparin. The experiments carried out by Kwak et al. showed that fucoidan from Fucus vesiculosus prolonged the activated partial thromboplastin time, but this effect was smaller than that of heparin. The conclusion of this study was that fucoidan from Fucus vesiculosus had less potent antithrombotic activities than heparin in vitro. For instance in inhibiting thrombin and factor Xa activities and prolongating the activated partial thromboplastin time, it scored less than heparin. The only experiment in which fucoidan scored better than heparin was in the inhibition of ADP-induced platelet aggregation.

In the study carried out by Dürig et al. 1997, the Wilcoxon test for paired non parametric data was used to determine whether the results were statistically significant (p<0.05). This study was designed to test the impact of the molecular weight and sulfate content of fucoidan from Fucus vesiculosus on the anticoagulant activity of fucoidan. The conclusion of the platelet aggregation assay was that if the sulfate level remained constant and the molecular weight increased, the high molecular weight fucoidan from Fucus vesiculosus increased platelet aggregation significantly (p<0.05) more than low

molecular weight fucoidan. The experiment in which the activated partial thromboplastin time, α2– antiplasmin activity and plasminogen activator inhibitor activity were measured showed that if the molecular weight of the fucoidan remained constant and the sulfate level increased, then the anticoagulant effects increased, whereas the α2-antiplasmin inhibitor activity and plasminogen activator inhibitor activities decreased.

In contrast with the other studies on the anticoagulant activity of fucoidan from Fucus vesiculosus in vitro, the study by Dürig et al. 1997 concluded that fucoidan could also stimulate coagulation. However, Kwak et al. reported that fucoidan with low molecular weight only slightly stimulated coagulation and even has anticoagulant activities; which is consistent with the other studies described above.

In the study performed by Cumashi et al. 2007, the statistical significance (p<0.05) of the results was determind using the Student t-test. The experiments showed that the anticoagulant activity of 1 mg fucoidan from Fucus vesiculosus was equal to that of approximately 9.4 U heparin and that fucoidan from Fucus vesiculosus did not inhibit the platelet aggregation induced by thrombin significantly.

Most of the experiments were done with human plasma or platelets (only once with rabbit platelets). The activity was compared amongst others with heparin. Ex vivo studies are the next step to confirm the antiplatelet activity of Fucus preparations or concentrates. There are no direct consequences for the therapeutic indication of the monograph. Indirectly, interference with blood coagulation could be seen as an advantage in patients with overweight and at cardiovascular risk. However, the in vitro activity is clearly inferior to that of heparins and there is no guarantee for an in vivo effect.

•Inhibition of reverse transcriptase activity of HIV by fucans

The study carried out by by Quieroz et al. 2008) did not mention if an analysis to determine the statistical significance of the results had been performed. The results showed that galactofucan, fucoidan and fucan B from Fucus vesiculosus inhibited reverse transcriptase concentration dependently. Fucoidan had the strongest inhibiting acitivity of reverse transcriptase: 0.5 µg/ml fucoidan inhibited reverse transcriptase for activated DNA by 84.0 ± 4.3% and for synthetic polynucleotides by 98.1 ± 4.5%. As no positive controls were used, it is difficult to estimate the value of the experiments.

•Effects on the immune system

The study carried out by Oomizu et al. 2006 used one-way and two-way ANOVA, Bonferoni’s post test and the Student t-test to determine whether the results are statistically significant (p<0.05). The result from the study by Oomizu et al. showed that fucoidan from Fucus vesiculosus significantly (p<0.01) inhibited the release of IgE by B cells in vitro However, only one, rather high concentration was used, without any concentration-effect relationship. The relevance of the results is limited.

The study carried out by Price et al. 2002 showed that Fucus vesiculosus extracts inhibited histamine release from mast cells in vitro by approximately 58%. Again, no concentration dependence was investigated, which reduces the importance of the observations.

In the study by Choi et al. 2005, the statistical significance (p<0.05) of the results was determined using analysis of variance combined with Dunnett’s test and Duncan’s multiple range test. When macrophages and lymphocytes were exposed to fucoidan from Fucus vesiculosus, the viability of macrophages and lymphocytes increased significantly (p<0.05) in vitro.

In the study by Kim and Joo 2008, the statistical significance (p<0.05) was determined using the Tukey-Kramer multiple comparisons test. This study showed that fucoidan from Fucus vesiculosus increased the viability of dendritic cells significantly (p<0.01). The production of IL-12 (p<0.01) and TNF-α (p<0.001) by fucoidan treated dendritic cells also was significantly higher, whereas the antigen uptake was significantly lower (p<0.05). TNF-α and IL-12 play important roles in the protection against pathogens. The significantly (p<0.001) increased expression of MHC class I and II, CD54 and CD86 on leukocytes suggested that fucoidan had immunostimulatory effects and stimulated the maturation of dendritic cells. However the concentrations to obtain the effect were too high to create persepctives in vivo.

As an overall conclusion on the effect of fucoidan and other extracts from Fucus vesiculosus on the immune system, it can be stated that the consequences are limited to experimental conditions. There is no direct relevance for the monograph.

•Fucoidan in atherosclerosis and restenosis prevention

Unfortunately the study performed by Kwak et al. 2010 did not mention any p-values. As a consequence it is unclear whether the results were statistically significant. The results from the study by Kwak et al. showed that fucoidan from Fucus vesiculosus decreased the production of several inflammatory cytokines by human umbilical endothelial cells in vitro. This suggested that fucoidan from Fucus vesiculosus had a qualitative potential in the prevention of atherosclerosis and restenosis, because in both processes inflammation plays a role. This study also showed that fucoidan from Fucus vesiculosus inhibited the proliferation, migration and adhesion of rat aortic smooth muscle cells in vitro more than heparin. However it should be noted that high concentrations were used which may be difficult to obtain in vivo.

In the study carried out by Cumashi et al. 2007, the statistical significance (p<0.05) of the results was determined using the Student t-test. The results showed that fucoidan from Fucus vesiculosus did not significantly inhibit the adhesion of polymorphonuclear leukocytes in vitro. The authors suggested that possible anti-inflammatory properties of fucoidan could not be explained by an anti-adhesive action on the polymorphonuclear leukocytes.

The significant decrease in persistence and accumulation of leukocytes in capillaries and venules, showed in the article by Ritter et al. 1998, indicated that fucoidan affected the adhesion process in a rat heart model after ischemia. However the observed effect was obtained with a high concentration.

•Effects on metastasis

In the study carried out by Cumashi et al. 2007, the statistical significance (p<0.05) of the results was determined using the Student t-test. The study showed that fucoidan from Fucus vesiculosus significantly (p<0.01) inhibited tumour-platelet interactions in vitro. The concentration needed for the effect was high and may not be realistic in vivo.

•Protection against irradiation-induced apoptosis

In the study by Byun et al. 2008, the significance (p<0.05) of the results was determined using the Turkey-Kramer multiple comparisons test. This study showed that in bone marrow fucoidan from Fucus vesiculosus selectively protected granulocytes from cell death due to irradiation (p<0.01) and deprevation of cytokines (p<0.05) in vitro. It also had significant (p<0.05) immunostimulatory effects by stimulating the production of IL-12 and TNF-α and increasing the number of granulocytes in vitro.

In the study performed by Rhee and Lee (2011), the statistical significance (p<0.05) was determined using life table methods with Mantel-Peto-Cox summary of Chi square. The results showed that the viability of cells that were treated with fucoidan from Fucus vesiculosus and then-irradiated increased significantly (p<0.05) compared to not fucoidan-treated cells.

The results of the study by Rhee and Lee 2011 were similar to those of Byun et al. 2008. They showed that the viability of γ-irradiated cells increased significantly (p<0.05) after treatment with high concentrations of fucoidan from Fucus vesiculosus.

•Effects of fucoidan on myotoxicity

(5)fucoidan control (different concentrations- see (2))

The study performed by Angulo and Lomonte (2003) showed a concentration-dependent effect. The activity of fucoidan may be due to insoluble complexes with phospholipase A2.

•Effect of fucoidan on tumour cell viability

Several studies about the induction of apoptosis in tumour cell lines have been performed. Most of them concern fucoidan from Fucus vesiculosus and one extract of Fucus vesiculosus.

The study performed by Aisa et al. 2005 did not mention if an analysis had been done to determine the statistical significance of the results. In spite of this, the article did mention that there was a significant (p<0.01) difference in growth between the control group and the group treated with 100 µg/ml

fucoidan from Fucus vesiculosus. Therefore, it is difficult to draw conclusions from this article. The in vitro study found that human lymphoma cells treated with fucoidan from Fucus vesiculosus proliferated less compared to the control group. This study also found that the cells treated with fucoidan from Fucus vesiculosus expressed more caspase-3 and less Rh123, GSK and ERK compared to control in vitro. The authors assumed that this changed expression was correlated with the increased apoptosis level of the cells.

In the study carried out by Hyun et al. 2009, every experiment was conducted at least three times and the statistical significance (p<0.001) of the results was determined using one-way ANOVA and Dunnett’s test. The experiments showed that concentrations of 10, 30, 50 and 100 µg/ml fucoidan from Fucus vesiculosus inhibited human colon carcinoma cell proliferation significantly (p<0.001). The experiments also suggested that there was a correlation between downregulation of Bcl-2, increasing concentrations of Bax and active ERK, p38 kinase, caspase-3,caspase-9 and the inhibition of the proliferation of the cancer cells all caused by fucoidan from Fucus vesiculosus. The conclusion of this study was that fucoidan from Fucus vesiculosus significantly (p<0.001) induced apoptosis in colon carcinoma cells in vitro.

In the study by Ale et al. 2011, Marine Drugs, the statistical significance (p<0.05) of the results was determined using analysis of variance. This study was designed to examine the effects of fucoidan from Fucus vesiculosus on melanoma B16 cells. The results showed that fucoidan significantly (p≤0.05) reduced the viability of melanoma B16 cells and according to the results this effect was, at least partly, achieved by a significant (p≤0.05) increase of apoptosis and caspase-3 activity The conclusion of this study was that fucoidan from Fucus vesiculosus significantly (p<0.05) inhibited growth and induced apoptosis in melanoma B16 cells in vitro.

In the study carried out by Choi et al. 2005, the statistical significance (p<0.05) was determined using ANOVA combined with Dunnett’s test and Duncan’s multiple range test. This study showed that addition of a combination of fucoidan from Fucus vesiculosus and macrophages or lymphocytes to YAC1 or B16 tumour cells caused significant (p<0.05) higher tumour cell death compared to control. The study also showed that compared to control the activity of myeloperoxidase and lysosomal phosphatase increased significantly (p<0.05) in macrophages treated with fucoidan. Both enzymes are produced by macrophages and play a role in phagocytosis. Furthermore fucoidan-treated macrophages produced significantly (p<0.05) higher amounts of TNF-α,IL-6, nitrite and H2O2. Nitrite is an indicator of NO production and NO and H2O2 are molecules which have cytotoxic effects. Both TNF-α and IL-6 play important roles in immunomodulation. The conclusion of this study was that addition of fucoidan from Fucus vesiculosus to macrophages and lymphocytes significantly (p<0.05) increased their ability to kill melanoma and lymphoma cells in vitro. The overall conclusion of these studies concerning the effect of fucoidan from Fucus vesiculosus on tumour viability was that fucoidan significantly (p<0.05) increased apoptosis in different tumour cell lines. The clinical significance is not clear.

•Effect on angiogenesis

on matrigel form structures that look like capillaries. To test the effect of fucoidan on this process, matrigel in the absence of growth factor was coated on wells. A suspension of HUVECs was put in the wells.

In the study performed by Cumashi et al. 2007, the statistical significance (p<0.05) of the results was determined using the Student t-test. The results of this study suggested that fucoidan from Fucus vesiculosus did not inhibit angiogenesis.

•Effects of fucophlorethols from Fucus vesiculosus on cyclo-oxygenase-1

The study performed by Parys et al. 2010 did not mention if a statistical analysis had been carried out. Therefore it is unknown if the results were statistically significant. This study showed that fucophlorethols from Fucus vesiculosus inhibited cyclo-oxygenase-1. The concentration needed for a relevant clinical effect may be too high to be realistic.

•Effects on inflammation

In the study carried out by Trento et al. 2001, the statistical significance (p<0.05) of the results was determined using the Dunnett’s test. The study showed that fucansulfate from Fucus vesiculosus significantly (p<0.01) decreased the number of polymorphonuclear lymphocytes that adhere to the rabbit aorta. This decrease suggested that fucansulfate from Fucus vesiculosus had an anti-

inflammatory effect by interacting with thrombin. It is not clear what may be the clinical relevance of this finding in vivo.

In vivo experiments related to the therapeutic indication of the monograph

•Effects on glucose levels

In the study performed by Roy et al. 2011, the statistical significance (p<0.05) was determined using the Student t-test. This study showed that the administration of phlorotannins from Fucus vesiculosus by gavage significantly (p<0.05) decreased the raise in the blood glucose after a meal compared to control. This could, at least partly, be due to the extended absorption caused by phlorotannins, which was observed in this study. Furthermore phlorotannins from Fucus vesiculosus also decreased the peak increase in insulin and the area under the curve for insulin, but these effects were not significant. In order to evaluate the therapeutic consequences, more clinical experience is needed. In the study carried out by Lamela et al. (1989) the statistical significance (p<0.01) of the results was determined using the Student t-test. The results of this study showed that extracts from Fucus vesiculosus did not have any significant effect on blood glucose levels.

The results of the study by Roy et al. 2011 were promising, but they are not concordant with the results of the study by Lamela et al. 1989, so the effect of Fucus vesiculosus on serum glucose levels needs further investigation.

In vivo experiments not directly related to the therapeutic indication of the monograph

•Effect on coagulation

In the study carried out by Trento et al. 2001, the statistical significance (p<0.05) of the results was determined using the Dunnett’s test. The results of this study showed that the decrease in blood pressure that was caused by thrombin was significantly (p<0.05) counteracted if fucansulfate from Fucus vesiculosus was administered intravenously before thrombin exposure. Furthermore the results of this study showed that if fucansulfate from Fucus vesiculosus was administered before an exposure to thrombin, the mass of the thrombus was significantly (p<0.05) lower compared to that of control. However this effect was lower than that of heparin.

In the study performed by de Azevedo et al. 2009, the statistical significance (p<0.05) of the results was determined using ANOVA and Tukey-Kramer test. This study showed that fucoidan from Fucus vesiculosus had significantly (p<0.05) lower hemorrhagic activity than heparin and low molecular weight heparin

The study carried out by Kwak et al. 2010 did not mention if an analysis to determine the statistical significance of the results had been performed. The experiment showed that the total time to occlude the left carotid artery in mice increased after the administration of fucoidan from Fucus vesiculosus. The concentration of fucoidan from Fucus vesiculosus that was needed to double the occlusion time compared to control was lower (0.54 mg/kg bw) than that of heparin.

Conclusion: The antithrombotic activity of fucoidan from Fucus vesiculosus seems to be comparable with heparin (high and low molecular weight) in the experimental models used. The question remains whether in clinical conditions improvements of hard endpoints will be obtained.

In the study performed by Veena et al. 2007, the statistical significance (p<0.05) of the results was determined using one-way ANOVA. The administration of ethylene glycol to rats induced oxidative stress, which damaged the epithelium of the kidney which then might induce the formation of stones. The results from this study showed that fucoidan from Fucus vesiculosus reduced the oxidative stress in the kidney by significantly (p<0.05) increasing the levels of antioxidant enzymes and non-enzymicanti-oxidants and significantly (p<0.05) reducing the levels of lactate dehydrogenase, glycolic acid oxidase and xanthine oxidase. The three latter enzymes are responsible for metabolising oxalate. Oxalate and his metabolites are free radicals which cause oxidative stress. Furthermore the results showed that fucoidan from Fucus vesiculosus significantly (p<0.05) reduced the levels of alkaline phosphatase, γ-glutamyl transferase and β-glucuronidase, which are all indicators of cellular damage. Whether fucoidan from Fucus vesiculosus could be used to prevent stone formation that is due to oxidative stress in the kidneys, remains to be clinically investigated, before any conclusion can be drawn.

•Effects on hormones

Progesterone levels did not change significantly for high 17β-estradiol rats.

In the study performed by Skibola et al. 2005, the statistical significance (p<0.05) of the results was determined using two-way ANOVA, Dunnett’s pairwise comparison and paired t-tests. This study showed that in rats dried, powdered Fucus vesiculosus significantly (p≤0.05) increased the number of days of estrous cycle as well as the number of days of diestrus phase within the estrous cycle (p=0.02). Furthermore Fucus vesiculosus also significantly (after 4 weeks p=0.02) reduced the serum 17β-estradiol levels. These results are consistent with the results of a study in 3 women (see Clinical data), but in that study dried, powdered Fucus vesiculosus also significantly (p=0.002) increased the plasma progesterone level. This could be due to the fact that in the studies with rats the blood was taken in the morning and in the morning the 17β-estradiol levels were at their peak, but the progesterone levels were not. This was a weakness of the study.

•Effects on the immune system

In the study by Ale et al. 2011, the statistical significance (p<0.05) of the results was determined using analysis of variance. The results of this study showed that fucoidan from Fucus vesiculosus significantly (p≤0.05) increased the natural killer cell activity compared to control. It can be questioned whether the modest increase with high doses of fucoidan creates perspectives for specific research.

•Inhibitory effect on muscle necrosis caused by snake venom

Unfortunately the study performed by Angulo and Lomonte 2003 did not mention if a statistical analysis had been carried out to determine the statistical significance of the results. Therefore it is unknown whether the results were statistically significant. This study showed that 135 kDa fucoidan from Fucus vesiculosus reduced the muscle necrosis in mice by 70 to 95% when fucoidan was preincubated with the snake venom Furthermore the study also showed that when 90 and 270 µg of fucoidan was injected intramuscularly in mice immediately after intramuscular injection of snake venom, the muscle necrosis was reduced by approximately 50%. The latter experiment resembled reality more than the first experiment. The authors concluded that even when fucoidan from Fucus vesiculosus is injected immediately after a snake bite, there still will be a lot of muscle necrosis. The relatively high molecular weight of this fucoidan may reduce its diffusion and distribution in the tissue. It may be useful to do experiments using lower molecular weight fucoidans to monitor their effect on muscle necrosis after a snake bite.

•Effects on serum triglyceride levels

In the study carried out by Lamela et al. 1989, the statistical significance (p<0.01) of the results was determined using the Student t-test. The results of this study showed that Fucus vesiculosus had no significant effects on serum triglyceride levels in New Zealand rabbits.

Fucoidan treated irradiated mice had significantly (p<0.05) less hypoplasia when compared to irradiated controls, the protective effect against hypoplasia increases with dose. All mice showed abnormalities in the lungs, liver and spleen after irradiation.

In the study performed by Rhee and Lee 2011, the statistical significance (p<0.05) was determined using ANOVA or the Bonferroni multiple comparison method. The results of the study by Rhee and Lee showed that fucoidan from Fucus vesiculosus significantly (p<0.05) increased the leukocyte and thrombocyte count 28 days after irradiation compared to control. Fucoidan also increased the erythrocyte levels and hematocrite levels and the survival time of the mice after irradiation compared to control, but these effects were not significant. The relevance of the statistical differences can be questioned, because of the high doses needed to obtain a reasonable survival.

There was no fecal blood, this means there were no lesions in the gastrointestinal tract.

The relative weight of kidneys raised in male rats that received high doses of extract 2 (25% rise), but the functional parameters of these organs were normal.

In the study by Zaragoza et al. 2008, the significance of the results was determined using the unpaired Student t-test and the one-factor analysis of variance. Although these statistical analyses were performed, the study did not mention the statistical significance of all of the results. The results showed that Fucus vesiculosus treated female rats ate 13% less than their controls. Furthermore the number of white cells shrank and α-amylase increased in groups that received extract 2 (to 50%) or high dose of extract 1 (to 70%) compared to control. However the coagulation parameters did not change and there was no fecal blood, the latter means there were no lesions in the gastrointestinal tract.

Although the Na+-excretion of the rats treated with extract 1 and 2 (68 and 90%, respectively) increased, the plasma [Na+] did not change. The study also showed that the relative weight of liver and kidneys increased in male rats that received high doses of extract 2 (25%), but the functional parameters of these organs were normal.

3.3. Overall conclusions on non-clinical data

A lot of in vitro studies have been performed with Fucus vesiculosus and its different components, such as fucoidan, phlorotannins and fucophlorethols. The subjects of these studies were very diverse, namely the effects on skin, cholesterol, oxidants, estrogen, progesterone, glucose levels, coagulation, viruses , immune system, atherosclerosis, restenosis, leukocyte recruitment, metastasis, irradiation of cells, snake venom, CYP1A, tumour viability, accumulation of advanced glycation end products, angiogenesis and cyclo-oxygenase-1. Most of these activities are not relevant for the therapeutic indication maintained in the monograph. They were nevertheless kept in the assessment report in order to give a large view on the herbal substance and its preparations.

Fucus vesiculosus extracts reduced trans-sialidase activity (which would be correlated to intracellular cholesterol accumulation), reduced 17β-estradiol levels and competed with estradiol and progesterone for binding to their receptors, reduces coagulation (inhibits the formation of thrombin and inhibits thrombin-induced platelet aggregation and plasminogen activator activity, increases activated partial thromboplastin time and prothrombin time) and inhibited the myotoxic effects on skeletal muscle cells after addition of snake venom.

Phlorotannins from Fucus vesiculosus inhibited α-amylase and α-glucosidase and inhibited the accumulation of advanced glycation products by scavenging reactive carbonyls.

However, the question remains whether the extract can reach the action site at a sufficient dose in vivo and if the in vitro models are representative for in vivo effects.

In vivo, phlorotannin from Fucus vesiculosus decreased the glucose level after gavage. Fucus vesiculosus increased the number of days in the oestrous cycle and reduced 17β-estradiol levels. Fucansulfate decreased thrombus formation and it also decreased the adherence of polymorphonuclear lymphocytes to the rabbit aorta (this is an anti-inflammatory effect), it inhibited kidney stone formation that was caused by oxidative stress by increasing the levels of several anti-oxidative enzymes, it reduced snake venom induced muscle necrosis if it was injected soon enough and it inhibited death of leukocytes and thrombocytes after irradiation and it increased survival time after irradiation. Fucoidan from Fucus vesiculosus increased natural killer cell activity. The results obtained with high doses are modest.

A difference has to be made between the effects obtained with Fucus vesiculosus preparations and the results from experiments with concentrated compounds from Fucus when considering traditional use.

There were no relevant signs of toxicity during the examination period for the used doses in the study conducted by Zaragoza et al. 2008. It would be useful to have more toxicity studies at our disposal. For example studies on genotoxicity, carcinogenicity, reproductive and developmental toxicity, immunotoxicity or other special toxicities were not performed. Despite the lack of these data, Fucus vesiculosus is used since centuries without severe documented toxicological responses.

CYP1A is a phase I enzyme, which is used in this experiment as a phase I marker enzyme. The study by Parys et al. 2009 showed that fucophlorethols from Fucus vesiculosus inhibited CYP1A activity. The meaning of these findings has no direct consequences for the monograph.

4.1.3. Dose response studies

No data available.

4.1.4. Clinical studies (case studies and clinical trials)

•Effect on blood cholesterol

The study of Aksenov et al. (2007) showed that Fucus extracts reduced the trans-sialidase activity significantly. The authors suggested that a reduction in trans-sialidase activity may play a role in the intracellular cholesterol accumulation. The hypothesis was based upon a biochemical reasoning and analogy with garlic. The correlation between the marked decrease of trans-sialidase activity and cholesterol levels in blood reported for garlic has so far not been confirmed for Fucus vesiculosus extracts (no measurement of cholesterol levels).

•Effects on skin

In the study by Fujimura et al. 2002, the statistical significance of the results had been determined using the paired Student t-test. Skin thickness increased and skin distension decreased with age. This study showed that the Fucus vesiculosus extract significantly (p<0.005) decreased skin thickness and significantly (p<0.005) increased skin distension. Whether Fucus vesiculosus may have relevant topical therapeutic effects remains to be demonstrated.

•Effects on weight management

There are no clinical studies with monopreparations of Fucus vesiculosus.

A clinical study with a commercial preparation containing pomegranate seed oil and brown seaweed extract was conducted in obese postmenopausal women with a non alcoholic fatty liver disease, and women with normal liver fat. The authors reported that the preparation was able to reduce body weight, body and liver fat content, and plasma C-reactive protein (Abidov et al. 2010). No further details are given as the study does not match the substance/preparation that is subject of the monograph. There was a conflict of interest in the article of Abidov et al. 2010; furthermore it was not specified which brown seaweed the product contains. This was not found on the manufacturer’s website. Statistically, there was no correction for multiple testing and no exact p values were provided.

•Effects on osteoarthritis of the knee

There are no clinical studies with monoprearations containing Fucus vesiculosus.

A study was conducted with a commercial preparation containing 3 species of brown algae including Fucus vesiculosus in a limited number of patients with osteoarthritis of the knee. The preparation reduced the comprehensive osteoarthritis test score (Myers et al. 2010). No further details on this study are given as the herbal preparation does not match the substance/preparation that is subject of the monograph. It was an open-label pilot study. It was not clear whether the visual analogue scale was validated. A one-tailed test was used to calculate significance. The authors did not correct for multiple testing.

•Effects on oestrogen, progesterone and menstrual cycle

In the study performed by Skibola 2004, the statistical significance (p≤0.05) of the results was determined using unpaired t tests. This study reported that in three women 700 and 1400 mg dried, powdered Fucus vesiculosus significantly (p≤0.05) increased the menstrual cycle length and significantly (p≤0.05) reduced the days of menstruation. For patient 1, the plasma estradiol levels were significantly (p≤0.05) lower and the progesterone levels were significantly higher (p=0.002 after high dose treatment) when compared to the levels before treatment. The higher dose induced higher effects. However the doses applied can be discussed, when considering the possible amount of iodine ingested (see chapter 5.3). In general, these results are of limited value.

4.1.5. Clinical studies in special populations (e.g. elderly and children)

No data available.

4.2. Overall conclusions on clinical pharmacology and efficacy

An aqueous extract of Fucus vesiculosus decreased skin thickness and increased skin distension. The powdered herbal substance decreased plasma estradiol levels and increased menstrual cycle length and reduced the number of days of menstruation in a trial with three patients. A commercial

combination preparation including a preparation of Fucus vesiculosus showed beneficial effects in weight management of postmenopausal women. Another commercial combination extract was reported to reduce the complaints of osteoarthritis of the knee.

The value of these clinical studies is limited. Variable inclusion criteria were used to include patients and the patients investigated are not directly representative for the target population in relation to the indication found in the monograph. For the intervention, mixed preparations and sometimes high doses were used, which should be reconsidered when taking into account the amounts of iodine possibly ingested. Most of the outcomes are not related to the therapeutic indication of the monograph.

5. Clinical Safety/Pharmacovigilance

5.1. Overview of toxicological/safety data from clinical trials in humans

•Effects on thyroid gland

The findings of the study by Clark et al. 2003 on the influence on thyroid hormones are similar to trials with iodine supplementation. This indicates that the iodine present in bladderwrack products is bioavailable. They were not corrected for multiple testing (some results can become not significant if corrected for multiple testing). The increase of TSH and reduction of T3 by the Fucus preparation points to a possible inhibition of the thyroid function due to the content of iodine in the capsules (660 µg up to 4 times daily).

5.2. Patient exposure

No data available.

During the assessment, reference was made to the specified conditions of use for orlistat as an OTC medicine, according to which treatment is limited to 6 months.

5.3. Adverse events and serious adverse events and deaths

The chapter on adverse events and serious adverse events and deaths is subdivided into a general part on iodine in the environment and recommendations for daily intake. A second part considers possible side effects of Fucus containing preparations.

5.3.1. Iodine in the environment and recommendandations for intake

General considerations

According to the information in the SPC of iodine containing medicines in some European countries (e.g. Germany) patients should not use Fucus vesiculosus in case of the following conditions: (1) pathologies of the thyroid gland; (2) cardiovascular pathologies e.g. recent myocardial infarction, coronary disease, angina pectoris, hypertension; (3) adrenal insufficiency; (4) women suffering from postmenopausal osteoporosis.

Fucus vesiculosus ingestion could create collecting duct or inner medullary defects which is the onset of diabetes insipidus. Fanconi’s syndrome has been reported after ingestion of Fucus vesiculosus. Consumption of Fucus vesiculosus grown in a contaminated environment, for example with arsenic or heavy metals, can lead to ingestion of these toxic entities. This can cause glomerular injury which is manifested in proteinuria and hematuria (Luyckx and Naicker 2008, Barnes et al. 2007).

There are serveral case reports on Fucus vesiculosus. One on arsenic toxicosis in a 54-year-old woman (Amster et al. 2007); this case report however is objected by an employee of a trade association that represents the natural products industry (Fabricant 2007). Moreover there were two cases of elevated urinary excretion of arsenic caused by the intake of food supplements containing bladderwrack (Walkiw and Douglas 1975). Finally there is one report on therapy failure of iodine-131 due to high iodine intake from selenium supplements. These supplements contained bladderwrack as an additive (Arum et al. 2009).

With regard to therapeutic use of Fucus vesiculosus, the discussion is mainly related to the ingestion of iodine, added to the daily amount provided by food and environment.

algae and can have an extremely high iodine content, particularly in marketed products derived from dried material (up to 6,500 mg iodine/kg dry product). A product known as Kombu-powder contains about 0.5% iodine (EFSA 2006). Hence there is a need for well-qualitatively and quantitatively defined herbal preparations.

Daily intake of iodine

The daily intake of iodine from diet sources may vary from country to country (Fig. 4).

In Germany, the median daily iodine intake varies from about 64-118 (mean: 45.3) μg I/day for males aged 4-75 years and from 59-114 (mean: 44.2) μg I/day for females aged 4-75 years. For infants aged 6 months, children and young adults up to the age 18 years the mean iodine intakes varied from 31-64 μg/day for males and from 28-56 μg/day for females. In those taking iodine supplements once/week the corresponding mean levels were 124 μg I/day for males and 109 μg I/day for females compared to 107 μg I/day for males and 102 μg I/day for females not taking any supplements.

In Denmark, the median intake was about 119 μg I/day for males and 92 μg I/day for females.

In The Netherlands, the median intake was about 145 μg/day for males and 133 μg/day for females.

In Great Britain, the median dietary intake from all sources was 226 μg/day for males and 163 μg/day for females, the 97.5th percentile reaching 434 μg/day in males and 359 μg/day in females. Survey data in young children aged 1½-4½ years show for high milk consumers in winter 247 μg/day to

309 μg/day (EFSA 2006).

According to Andersson et al. (2007), iodine intake is optimal in 20 European countries (between 100 and 199 µg/day), whereas 11 countries have a mild to moderate iodine deficiency. Only Macedonia has a risk of iodine-induced hyperthyroidism with a mean intake of more than 200 µg/day (Fig. 4).

Bladderwrack (kelp) contains, according to the European Pharmacopoeia 7.0, between 0.03 and 0.2% iodine on dried substance. This implies that Fucus vesiculosus preparations may contribute to the dietary iodine intake.

The World Health Organization advises a daily iodine intake of 100 to 150 µg. Some countries or organisations advise daily iodine intake levels up to 200-300 µg. During pregnancy and lactation there is an increased urinary loss of iodine caused by a higher renal blood flow. Therefore a higher daily iodine intake is advised (up to 230 µg) (SCF 2002).

According to some sources doses exceeding 150 µg iodine per day may cause the side effects of increased thyroid gland function such as heart palpitation, increased heart rate, trembling, changes in blood pressure and increased basal metabolism, though rarely reported. High iodine intake can also cause aggravation of acne. Therefore long-term use in subjects with normal thyroid function should be avoided. A generalised allergic reaction can occur (Yarnell and Abascal 2006, Verhelst 2010, Barnes et al. 2007). However this information is not in line with reports about about intake of high doses.

The parameters altered in dose-response studies included an elevation of serum TSH levels in response to iodine intake and the enhanced response in TSH levels to TRH stimulation. They were all of a biochemical nature and not associated with any clinical adverse effects. However, elevated serum levels of TSH are not necessarily clinically adverse, but could be regarded as indicators of an existing risk of induced hypothyroidism. There is uncertainty whether the subtle changes observed, such as an enhanced response to TRH, would have significant adverse biological consequences even if sustained over longer periods, because all observed values remained within the normal ranges for the parameters determined. It remains uncertain whether chronic exposure to these small doses would have any relevant clinical consequences in normal euthyroid individuals (EFSA 2006).

An upper limit (UL) can be established on the basis that the noted biochemical changes in TSH levels and the TSH response to TRH administration were marginal and unassociated with any clinical adverse effects at estimated intakes of 1,700 and 1,800 μg/day. Although the studies on which these UL estimates are based were all only of short duration, involved only a small number of individuals, and lacked precision of the actual total dietary intakes, their results were supported by the study covering a 5-year exposure at approximately similar iodide intake levels of 30 μg/kg bw/day (equivalent to approximately 1,800 μg iodide/day) in which no clinical thyroid pathology occurred. A safety factor of 3 is thus considered adequate and provides an UL for adults of 600 μg/day. The UL of 600 μg is also considered to be acceptable for pregnant and lactating women based on evidence of lack of adverse effects at exposures significantly in excess of this level. Since there is no evidence of increased susceptibility in children, the ULs for children were derived by adjustment of the adult UL (Table 6) on the basis of body surface area (body weight 0.75) (EFSA 2006).

In the US the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board together with Health Canada are pursuing a joint project which proposes a tolerable upper level of intake for iodine for adults of 1,100 μg/day. WHO has suggested a provisional maximum tolerable daily intake of 1 mg/day from all sources, equivalent to 17 μg/kg bw. In countries with long-standing IDD the intake should not exceed 500 μg/day to avoid the occurrence of hyperthyroidism. In France, the Expert Committee on Human Nutrition has suggested an UL of 500 μg I/day in countries with long-standing Iodine Deficiency Disease to avoid the occurrence of hyperthyroidism (EFSA 2006).

Upper levels of tolerance and toxicity of iodine

Very high doses are required to reach the toxic levels of iodine. Chronic iodine intake can cause iodism, the doses at which this occurs differ and were not determined. Sensitivity to iodine-induced hyperthyroidism is race-dependent, for example the Japanese and African populations appear to be less sensitive. Studies conducted on subchronic exposure of iodine deal with the same problem. Supplements up to 3 mg appeared to have no effect on serum TSH levels, whereas 50 to 250 mg significantly increased these levels, however the effect was small after 10 to 14 days intake. These studies did not evaluate the dietary iodine intake. Therefore total iodine intake remains unclear. One single dose of 2,000 to 3,000 mg of iodine is probably lethal to humans (SCF 2002).

5.3.2. Possible side effects with

Fucus

containing preparations

Bladderwrack (kelp) can concentrate various heavy metals. Auto-immune thrombocytopenic purpurea and disorderd erythropoiesis in a patient who had been taking kelp for 6 weeks was attributed to the arsenic content of the preparation (Pye et al. 1992).

Clinical hyperthyroidism has also been reported in patients taking kelp-containing preparations as part of a slimming regimen or dietary supplement (Eliason 1998).

The FDA has advised that preparations containing compounds such as kelp, which may be taken orally in bulk laxatives or weight-control preparations should be taken with a full glass of water or, if the patient has difficulties in swallowing, they should be avoided. Such compounds will swell into masses that may obstruct the oesophagus if not taken with sufficient water (Sweetman 2009). This information has been only partially implemented into the monograph, as the selected posology is restricted and the pharmaceutical form facilitates swallowing.

5.4. Laboratory findings

No data available.

5.5. Safety in special populations and situations

Fucus vesiculosus is contra-indicated in following cases: hyperthyroidism, Graves or Basedow disease, Hashimoto thyroiditis, after partial resection of the thyroid gland, excess of iodine, pregnancy or lactation, children under five years, hypersensitivity to halogens, malicious diseases and tuberculosis (Zimmermann and Delange 2004, Barnes et al. 2007, De Smet et al. 1993, De Smet et al. 1997).

In contrast, other literature considers the interaction with vitamin K-antagonists unlikely (Williamson 2009).

One case report of hyperthyroidism was published about a 60-year-old male patient diagnosed with bipolar disorder and under treatment with lithium. Since his myocardial infarction in 2001, the patient was treated with ramipril (1.25 mg 2 times daily), bisoprolol (2.5 mg/day), simvastatine (10 mg/day) and acetylsalicylic acid (100 mg/day). He was operated several times for an anal fistula, which is why he started taking a herbal product that contained besides 0.125 g of Fucus vesiculosus also Rhamnus purshiana 0.170 g and Frangula 0.222 g per tablet. The patient took this preparation regularly (once a day). The thyroid hormones were controlled every 4 months. In 2008, he developed hyperthyroidism: T4: 2.13 ng/dl (normal levels 0.9-1.7) and TSH 0.01 mIU/l (normal levels 0.27-4.2). The condition was treatable with metamizole and thyroxine (Arbaizar and Llorca 2011).

5.6. Overall conclusions on clinical safety

The quality of Fucus preparations should be carefully controlled, especially as heavy metals are concerned. Although there is some case reporting (among others on interaction between lithium and Fucus) and data about the endocrinological consequences of the intake of iodine are available, there are no alarming signals from pharmacovigilance or intake of iodine from food. Although a maximum iodine content should be considered for the extracts, it is not clear what may be the threshold. Apart from an upper limit, it is highly recommendable to set limits to the duration of treatments and to recommend regular monitoring (e.g. every 4 months) of thyroid function.

6. Overall conclusions

Quality

The quality of the herbal substance and its extracts must be guaranteed, especially as contaminations with heavy metals are concerned. Furthermore the total iodine content should be known and the permitted daily intake should not be exceeded.

Safety

It has been demonstrated that the intake of iodine-containing Fucus preparations can influence thyroid function. The maximum content of iodine is 0.2%, according to the monograph in the European Pharmacopoeia. The amount of iodine by intake of Fucus vesiculosus adds to the daily intake from food. Therefore a maximum intake is defined to guarantee a safe use as the regular intake enhanced with the iodine from Fucus. The resulting intake of total iodine should not exceed the upper limit defined by EFSA of 600 µg (see also benefit-risk). A maximum daily limit of 400 µg iodine intake by Fucus was defined in the monograph, taking into account that in Europe the dietary intake of iodine is considered to be mostly suboptimal.

Efficacy

Based upon market information provided by the members, a traditional use of powdered herbal substance of Fucus vesiculosus as an adjuvant in slimming diets can be granted, and a corresponding monograph can be conceived. However some conditions should be considered with regard to the maximum daily intake of total iodine and the duration of treatment. There are a few clinical data on the use of combined preparations containing Fucus. The outcomes of these studies cannot be translated to the monograph. While there is no evidence for a well established use, traditional use can be granted for the monopreparation.

Although cardiovascular, immunological, endocrinological, anti-oxidative and anti-tumour activities Fucus and its components have extensively been studied preclinically, currently, the findings of these studies are not seen relevant for the traditional therapeutic indication of the actual monograph.

Benefit-risk

The benefit-risk analysis remains positive for Fucus vesiculosus, provided that the total intake of iodine does not exceed 600 µg/day. For this reason, it is specified in the monograph that the upper daily limit of 400 µg total iodine per day following intake of Fucus vesiculosus containing medicinal products should not be exceeded.

Therapeutic area for browse search

Overweight, weight loss, adjuvant.

List entry

Due to the lack of genotoxicity testing, no List entry can be established.